Sildenafil (WO94/28902) developed by Pfizer Inc. is an oral PED5 inhibitor for treating male erectile dysfunction. It increases the level of cGMP, an enzyme substrate of type V phosphodiesterase (PDE5), in smooth muscle cells to relax the smooth muscle and induce vasodilatation by inhibiting the type V phosphodiesterase, so as to increase the flow rate of blood in the smooth muscle to induce erection.
From then on, many big pharmas and research teams have developed a lot of PED5 inhibitors with other different chemical structures. WO98/49166, WO99/54333 and WO 01/87888 disclose another series of pyrazolo[4,3-d]pyrimidin-7-one derivatives; WO2004/096810 discloses a series of 5,7-diaminopyrazolo[4,3-d]pyrimidine compounds; WO2004/108726 discloses a series of dihydropyrrolo[2,3-d]pyrimidin-4-one compounds; WO2004/101567 discloses a series of imidazo[1,5-a]-1,3,5-triazin4(3H)-one compounds; WO2006/126081, WO2006/126083, WO2007/020521 and CA02339677 disclose a series of pyridinopyrazinone compounds; WO2005089752 discloses a series of tetracyclic carboline compounds; WO2005/012303 and WO2007/002125 disclose a series of xanthine derivatives; and WO03/020724 discloses a series of polycyclic guanidine xanthine compounds. All of these compounds also show strong inhibitory activities of PDE5.
The developing PDE5 inhibitors are also used for pulmonary hypertension, diabeticgrastrointestinal disorder, insulin resistance, hyperlipemia and the like.
Although sildenafil has achieved a good clinical effect, it shows some side effects, such as headache, facial flushing, upset stomach, nasal obstruction, blurred vision, sensitivity to light, bluish vision and the like in clinic, since it also has inhibition on other PDE isoenzymes to the different extent. On the one hand, as the side effects are dose-dependent, there is a need for a PDE5 inhibitor having a stronger activity to decrease the dose and alleviate the side effects; on the other hand, since the vision disorders is caused by inhibition of type VI phosphodiesterases (PDE6) existing in retina, it is another object in finding out a new PDE5 inhibitor to increase the selectivity, especially against PDE6.